Dendritic cells in the skin (Langerhans cells) form a dense network of “sentinels” that act as first line of defense of the immune system.1

There’s a lot of interest in using dendritic cells as vaccines these days. A paper in PLoS One2 offers a cautionary note.

Dendritic cells (DC) are the main cell type that drive T cells from their normal naive state to an active state. In the naive state, a T cell can recognize its target, but doesn’t do anything about it; in the active state, the T cell does something, ranging from spreading inflammation to killing infected cells, and so on. The DC is needed to bridge these states. DC do many things, but at the simplest level they connect the presence of an antigen (a T cell target, in this case) with the presence of something dangerous or abnormal — a pathogen, or tissue damage.

There are some conditions where we’d like an immune response, where DC don’t detect one or the other of their components (i.e. antigen or danger). For example, there may be a situation that we know is dangerous, but where there’s little evidence of “danger” for the DC. A vaccine, for example, doesn’t want to deliver a huge amount of tissue damage, but we’d still like to get a strong response to an antigen. For a natural situation, cancers are often ignored by the immune system even though there may be lots of cancer antigens, and one reason (of many) for this ignorance is that the DC may not perceive a lot of danger in the context of the cancer.

So why not take the DC out of the system, alarm them with some danger information in the test tube, load them up with antigen, and then return them to the body? That’s called a dendritic cell vaccine, and there’s fairly intense interest in the approach.

There’s been some success using this approach, but perhaps less than you’d expect from the biology as we understand it.

Several clinical trials conducted over the past decade have demonstrated that DC vaccines can prime and boost antigen-specific CD8+ T cells in humans. However, their clinical efficacy remains to be definitively demonstrated [6], [19], [20], [21]. The lack of success has been variously attributed to several factors: administration of relatively low cell numbers of DCs, suboptimal route of administration, improper antigen dose, poor choice of antigenic targets, unsuitable maturation state of DCs, and inappropriate frequency of injections. However, understanding exactly which of these concerns represent true problems may be difficult because little is known regarding the fate and function of ex vivo generated DCs after they have been injected 2

Yewdall et al asked what happens to DC after they’re given this course and returned to the patient (mice, in this case). Their surprising conclusion is that the DC don’t work to prime T cells directly. Instead, they have to hand off their antigens to other cells in the body that have never left:

Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. … This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs. 2

As always in science, a single paper needs to be confirmed by others, so we won’t get too distressed until we see if other groups replicate this, and if it’s a universal truth or something specific to the particular system these authors were looking at. (And, of course, this doesn’t trump actual evidence of efficacy for DC vaccines.) My own suspicion is that the work is accurate but limited, and there’s something about this particular system which prevented the transferred DC from being good primers; but as I say, I’d like to see some followup from another group.

[…] DCs are removed, activated and loaded with antigen, and returned to the body. The observation that DC vaccines have an insignificant role in directly priming CD8+ T cells may cast a shadow on this […]

How important are DCs in triggering CD8+ T-cell responses under normal circumstances? My understanding was that they were more important in the CD4+ T-cell responses, but that they could sometimes transfer MHC1-bound antigen from other host cells to CD8+ T-cells to trigger a response. Intuitively, if the MHC1-bound antigen the CD8 cells are reacting to comes from some process inside the infected cells (like some enzyme a virus needs for replication), it's hard to see how the DC would ever find and present that antigen unless it was infected itself.